This is a revised application entitled Sex/Gender Factors in Nicotine Addiction submitted in response to PA-07-329. Cigarette smoking is one of the most prevalent addictive disorders and is associated with a number of debilitating diseases (e.g., lung cancer, stroke, cardiovascular and respiratory disease, osteoporosis) that result in an estimated 438,000 deaths each year. Sex and gender factors in nicotine addiction are poorly understood, and we hypothesize that the hormonal milieu is one critical influence on the abuse-related effects of smoking. We propose preclinical behavioral studies to determine how sex and menstrual cycle phase influence nicotine self-administration, and how acute and chronic treatment with neuroactive gonadal steroid hormones (estradiol, testosterone and progesterone) alters the reinforcing effects of nicotine. Nonhuman primates are excellent models of drug self-administration and neuroendocrine control of the macaque menstrual cycle is very similar to that of women. Nicotine self- administration will be maintained on a progressive-ratio schedule that requires an increasing number of responses for successive nicotine injections. The dependent variables will be the number of nicotine injections self-administered, the rate of operant responding, and the progressive ratio break point, i.e., the ratio at which animals stop responding for nicotine. In studies designed to examine the influence of sex and the menstrual cycle on nicotine self- administration, progesterone and estradiol levels will be measured to objectively define phases of the menstrual cycle and to distinguish between ovulatory and anovulatory menstrual cycles. We hypothesize that females will self-administer more nicotine and reach higher break points on a progressive ratio schedule than males. Next, we will examine the effects of acute and chronic treatment with neuroactive gonadal steroid hormones (estradiol, testosterone and progesterone) on nicotine self-administration dose-effect curves in gonadectomized males and females where basal steroid hormone levels are low. We hypothesize that estradiol and testosterone will enhance the reinforcing effects of nicotine, and that progesterone will attenuate the reinforcing effects of nicotine in females to a greater extent than in males. Steroid hormone receptor antagonists will be used to determine the hormone specificity of behavioral effects observed. Finally, the reinforcing effects of gonadal steroid hormones alone will be compared in males and females before and after gonadectomy. The neuroactive steroid hormones provide a novel approach to the treatment of a number of psychiatric disorders as well as drug abuse. The proposed studies may translate into new and more effective approaches to the treatment of nicotine addiction and will advance our understanding of its basic neurobiology. PUBLIC HEALTH RELEVANCE: Addiction to cigarette smoking is a major public health problem that is associated with many debilitating and lethal disorders (lung cancer, stroke, cardiovascular and respiratory disease, osteoporosis), yet effective treatments remain elusive. We propose to study how sex and neuroactive gonadal steroids influence the abuse-related effects of nicotine (the main addictive component of tobacco) in males and females. We hypothesize that the neuroactive gonadal steroid hormones may offer a novel biologic approach to the treatment of nicotine addiction, in part because these neuroactive hormones are being used to treat a number of psychiatric disorders, including depression and anxiety, and may have therapeutic applications in drug dependence.